We have described CD4+CD25+ Treg cells in the cat and demonstrated that they are chronically activated in feline immunodeficiency virus (FIV) infected animals. Treg cells from FIV-infected cats significantly inhibited proliferation of CD4+CD25- T cells, and are apparently activated in vivo as a result of the chronic FIV infection. As activated Treg cells are non-antigen specific in their suppressive function, it is possible that these cells could in turn suppress or anergize CD4+ T helper responses to a variety of antigens including FIV antigen and thereby contribute to the acquired immunodeficiency syndrome (AIDS) characteristic of this infection. The same observation has recently been reported in HIV-1 infected people and interestingly, increased levels of Treg function were associated with a favorable clinical status or respose to HAART. Normally, Treg function is critical to limit and down-regulate immune responses, preventing excessive inflammation and autoimmune disease. Whether Treg cells in HIV infection are beneficial or detrimental is unclear and the answer may depend on the stage of disease. It is possible that HIV-induced Treg activity during acute infection may limit the scope and efficacy of the anti-viral response, whereas Treg activity during asymptomatic infection may serve to control chronic immune activation and limit availability of activated target cells. The most definitive way to address the significance of Treg function during HIV infection is to deplete Treg cells in an animal model. In these studies we will employ the FIV/cat model of HIV to: 1.) Determine whether depletion of Treg cells before or immediately after FIV infection results in a more effective anti-viral immune response, and 2.) Determine whether depletion of Treg cells during the asymptomatic phase of FIV infection results in the expansion of antiviral T-cell immunity and/or change in plasma viremia. Results from these studies will provide a clinical understanding of Treg function in HIV infection and will guide future approaches to modulate Treg function.